Phytosome: Drug Delivery System for Polyphenolic Phytoconstituents

1. Introduction

            Phytosomes, complex of natural active ingredients and phospholipid(s), increase absorption of herbal extracts or isolated active ingredients when applied topically or orally. Phytosomes are cell like structures which result from the stoichiometric reaction of the phospholipids (phosphatidylcholine, phosphatidylserine, etc.) with the standardized extract or polyphenolic constituents (like flavonoids, terpenoids, tannins, xanthones) in a non-polar solvent, which are better absorbed, utilized and as a result produce better results than conventional herbal extracts [1-3]. Phospholipids are the main building blocks of life and are one of the major components of cellular membranes. In general, they are considered as natural digestive aid and carriers for both polar and non-polar active substances [4, 5]. Most of phospholipids possess nutritional properties, like phosphatidylserine which acts as a brain cell nutrient, phosphatidylcholine which is important in liver cell regeneration. Soya phospholipids have lipid reducing effect and hydrogenated phospholipids serve as basis for preparation of stable liposomes because of their amphiphilic charater [4, 6].

            Many plant extracts and phytochemical constituents possess excellent biological activity in vitro, but demonstrate less or no in vivo activity due to inherent property of drug constituents like poor lipid solubility, improper molecular size, destruction in gut, etc. [1]. These problems lead to decreased absorption. Decreased absorption problems can be alleviated by preparing complexes with phospholipids. Thus, phytosomal formulations enhance the bioavailability of active phytochemical constituents as they are now permeable and can cross the lipid rich bio-membranes quite easily, and the active components of the herbal extracts are well protected from destruction by digestive secretions and gut bacteria.Therefore, with help of phytosomal preparations, the amount of standardized plant extracts and phytoconstituents administered in body through several routes are required in less amount for good therapeutic activity [2].

            With the advancements in science, the phytosomes have gained importance in various fields like pharmaceuticals, cosmeceuticals and nutraceuticals in preparing different formulations such as solutions, emulsion, creams, lotions, gels, etc. Several companies involved in production and marketing of phytosomal products are Indena, Jamieson natural resources, Thorne Research, Natural factors, and Natures herb [7]. Some of the marketed formulations are shown in Table 1.

Table 1.Marketed Phytosomal Products.

2. Phytosome vs liposome: similarities and differences

            A liposome is formed by mixing a water-soluble substance with phosphatidylcholine. No chemical bond is formed; molecules of phosphatidylcholine collectively surround the water-soluble substance. Hundreds or even thousands of phosphatidylcholine molecules surround the water-soluble compound. In contrast, phytosome is formed by mixing a water-soluble substance with phosphatidylcholine and here chemical bond is formed between individual plant components and phosphatidylcholine. Soichiometric 1:1 or 2:1 complexes form which depend on the extract or phytoconstituent and the phospholipid used. This difference results in increased absorption of active constituents from phytosome than from liposomes [2, 3, 8, 9].

 Figure 1. Preparation of phytosomes.

3. Strenghts of phytosome [2, 4, 9-11]

v  Phytosomes show better stability as chemical bond is formed between phsospholipid molecule and phytoconstituent(s).

v  Dose of phytoconstituents is reduced due to more bioavailability of the phytoconstituents in the complex form.

v   Duration of action is increased.

v  Phytoconstituents complex with phospholipids are more stable in gastric sections and resist the action of gut bacteria.

v  Enhanced permeability of phytoconstituents across the biological membranes.

v  Absorption of lipid insoluble polar phytoconstituents through different routes shows better absorption, hence shows significantly higher therapeutic effects.

v  Phoshatidylcholine used in the formation of phytosomes, besides acting as a carrier also possess several therapeutic properties, hence gives the synergistic effect when particular substance is given.

v  Drug entrapment is not a problem with phytosome as the complex is biodegradable

4. Production methodology

            Phytosome, phospholipid complexes of vegetable extracts as shown in Figure 1 are prepared by adding the aqueous extracts to phospholipid dissolved in a suitable solvent such as ethyl acetate, acetone, ethanol under reflux and stirring. The resulting suspension is concentrated by reduced pressure to a thick residue which can be dried and ground. Natural, synthetic or semi-synthetic phospholipids have also been reported to form complexes with purified components of the vegetable extracts [8].

5. Principle

            Phosphatidylcholine (or phosphatidylserine) is a bifunctional compound. The phosphatidyl moiety is lipophilic and the choline (serine) moiety is hydrophilic in nature. This dual solubility of the phospholipid makes it an effective emulsifier. Thus, the choline head of the phosphatidylcholine molecule binds to these compounds while the lipid soluble phosphatidyl portion comprising the body and tail which then surrounds the choline bound material. Hence, the phytoconstituents produce a lipid compatible molecular complex with phospholipids, as shown (also called as phytophospholipid complex) [9].

6. Patents of phytosome technology

            Bioavailability of phenols in human volunteers was 3-5 times more when administered in complexed form with phospholipids (Oleaselected ^TM Phytosome^®) [12]. Phospholipids to olive fruits and leave extract ratio in the prepared complexes was in the range of 10 to 1%(w/w). Phospholipid complexes of curcumin provided five times higher peak plasma levels and AUC in male Wistar rats when compared to peak plasma levels and AUC value obtained after treatement with extract of uncomplexed curcumin [13]. Phospholipid complexes of proanthycynidins extracted from Vitis vinifera were prepared for use in suitable oral formulations, e.g. tablets or capsules, for treatment of atherosclerotic pathological conditions like myocardial and cerebaral infarctions [14].The phospholipid complexes of proanthocyanidin A2 (2:1 to 1:2 ratio) were significantly more useful for the prevention and the treatment of atherosclerosis lesions in rabbit [15]. Phospholipid complexes of extracts of Vitis vinifera, and phospholipid complexes of standardized extract from Centella asiatica were incorporated in pharmaceutical and cosmetic compositions for were described for prevention of skin aging [16].

            Flavanolignane-phospholipid complexes with a molar ratio of 1:1 of silybin, silidianin and silicristin were prepared for oral administration for treatment of acute or chronic liver disease of toxic, metabolic and/or infective origin or of degenerative nature, and for prevention of liver damages resulting from the use of drugs and/or luxury substances injurious to the liver [17]. The pharmacological activity of the novel flavanolignane-phospholipid complexes was more evident and demonstrated even when orally administered thus overcoming the known problems of absorption common to many phenolic substances and particularly to silymarin.

            Poor absorption by oral route, poor tolerability by cutaneous/topical administration and remarkable toxicity by parenteral route limits the therapeutic utility of saponins. Complexes of saponins with phospholipids allowed overcoming these drawbacks, particularly allowing an effective absorption by oral and topical route and a high stability, due to the lipophilic characteristics attained [18].Complex of flavonoids with phospholipids, characterized by high lipophilia and improved bio-availability and therapeutic properties as compared with free, not complexed flavonoids were prepared for use as the active principle in pharmaceutical and cosmetic compositions like tablets, capsules, creams, gels etc.[19]. Complexes of extracts from Krameria triandra Ruiz et av. and other plants of the Eupomatia genus, as well as some phenol constituents thereof of neo-lignane or nor-neolignane nature, with phospholipids were prepared [20] for incorporation in the traditional pharmaceutical forms for the treatment of superficial infected inflammatory processes, in torpid sores and in all the phlogistic conditions of the oral cavity.

            Complexes between natural or synthetic phospholipids and bilobalide, a sesquiterpene extracted from the leaves of Gingko biloba, were prepared for their application as antiinflammatory agents and as agents for the treatment of disorders associated with inflammatory or traumatic neuritic processes [21]. These complexes exhibited high bioavailability compared with free bilobalide, and were suitable for incorporation into pharmaceutical formulations for systemic and topical administration.

7. Conclusions

            Phytosomes results from the reaction of a stoichiometric amount of the phospholipid (phosphatidylcholine) with the standardized extract or polyphenolic constituents (like flavonoids, terpenoids, tannins, xanthones) in a non-polar solvent. Phytosomes show better absorption profile and enhances delivery of phenolic phytoconstituents to the tissues. The complexation of phenolic phytoconstituents and phospholipids makes the pheolic phytoconstituents more stable in the complex form due to liopophilic nature. Both improvement in absorption and increase of stability reduce the amount of active constituents required in formulating an appropriate dosage form when compared to the products obtained from conventional plant extracts. Hence, several excellent phenolic phytoconstituents have been successfully formulated and delivered in this way exhibiting remarkable therapeutic efficacy in animal as well as in human models. Numerous phytosomal products have been commercially introduced and churning out appreciable profits to the pharmaceutical, neutraceutical or cosmetic manufacturers.